Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action

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Abstract
The plasma level of NO x , i.e., the sum of NO 2 − and NO 3 − , is frequently used to assess NO bioavailability in vivo . However, little is known about the kinetics of NO conversion to these metabolites under physiological conditions. Moreover, plasma nitrite recently has been proposed to represent a delivery source for intravascular NO. We therefore sought to investigate in humans whether changes in NO x concentration are a reliable marker for endothelial NO production and whether physiological concentrations of nitrite are vasoactive. NO 2 − and NO 3 − concentrations were measured in blood sampled from the antecubital vein and brachial artery of 24 healthy volunteers. No significant arterial-venous gradient was observed for either NO 2 − or NO 3 − . Endothelial NO synthase (eNOS) stimulation with acetylcholine (1–10 μg/min) dose-dependently augmented venous NO 2 − levels by maximally 71%. This effect was paralleled by an almost 4-fold increase in forearm blood flow (FBF), whereas an equieffective dose of papaverine produced no change in venous NO 2 − . Intraarterial infusion of NO 2 − had no effect on FBF. NOS inhibition (N G -monomethyl- l -arginine; 4–12 μmol/min) dose-dependently reduced basal NO 2 − and FBF and blunted acetylcholine-induced vasodilation and NO release by more than 80% and 90%, respectively. In contrast, venous NO 3 − and total NO x remained unchanged as did systemic arterial NO 2 − and NO 3 − levels during all these interventions. FBF and NO release showed a positive association ( r = 0.85; P < 0.001). These results contradict the current paradigm that plasma NO 3 − and/or total NO x are generally useful markers of endogenous NO production and demonstrate that only NO 2 − reflects acute changes in regional eNOS activity. Our results further demonstrate that physiological levels of nitrite are vasodilator-inactive.